Found in watermelon …

Citrulline Retards Aging
And constrains serious metabolic disturbances

By Will Block

Aging is strongly associated with serious metabolic disturbances, and L-citrulline (hereafter citrulline)—an amino acid found in watermelon (the Latin term is citrullus)—may constrain these disorders.1

Worldwide human lifespan is increasing, and its progress will endure if science continues to proffer solutions to age-related diseases and disabilities. That’s because impaired metabolism and changes in body composition contribute greatly to declining health in the elderly population.

Sarcopenia and Fat Mass Accumulation

The loss of muscle mass, strength, and performance (sarcopenia)—which begins in middle age and worsens progressively—is associated with mobility disorders, increased risk of falls and fractures, impaired ability to perform activities of daily living, and increased risk of death.

Muscle loss is also often associated with fat mass accumulation, which plays a major role in metabolic disturbances (insulin resistance, low-grade inflammation, and dyslipidemia), thus further accelerating the aging process.

Many human studies report that nitric oxide (NO)—work about this molecule was awarded a Nobel Prize in 1998—improves sport performance. This is because NO is a modulator of blood flow, muscle energy metabolism, and mitochondrial respiration during exercise. Citrulline is an amino acid present in the body and a potent endogenous precursor of L-arginine (hereafter arginine), which is a substrate for NO synthase (see Fig. 1).


Oral citrulline and arginine increase
plasma arginine levels more
effectively in humans when
combined.


Oral Citrulline Plus Arginine …

In the scientific paper referenced in the first paragraph,1 researchers investigated the effects of combining 1 g of citrulline and 1 g of arginine as oral supplementation on plasma arginine levels in healthy male rats. Oral citrulline plus arginine supplementation more efficiently increased plasma arginine levels than 2 g of citrulline or 2 g of arginine, indicating that oral citrulline and arginine increase plasma arginine levels more effectively in humans when combined. This applauds the value of formulating a nutritional supplement with both of these amino acids. (See “Putting More Power into Your Life” in the April 2006 issue of Life Enhancement.)

Figure 1 The NO Pathway. One of these is a pathway that produces NO, and in that reaction, arginine is again converted to citrulline but by an entirely different mechanism that does not involve ornithine. Once citrulline is produced by any mechanism, it has only one place to go, metabolically speaking, and that’s back to arginine.
LEM1703Fig1_274.jpg
(click on thumbnail for full sized image)

The aim of this work was to evaluate the long-term effect of citrulline supplementation on metabolism in aged rats without health problems. Twenty-month-old male rats were randomly assigned to be fed as much as they desired (ad libitum) for 12 weeks with either a citrulline-enriched diet (1 g/ kg/day) or a standard diet. Motor activity and muscle strength were measured, body composition was assessed, and muscle metabolism (protein structure, mitochondrial exploration, and transductional factors) and lipid metabolism (lipoprotein composition and sensitivity to oxidative stress) were explored.

Compared with the standard-diet group, citrulline supplementation was associated with lower mortality (0% vs. 20%), 9% higher lean body mass, and 13% lower fat mass. Compared with the standard-diet group, citrulline-treated rats had greater muscle mass (+14–48%, depending on the type of muscle). Susceptibility to oxidation of lipoproteins, as measured by the maximal concentration of 7-ketocholesterol after copper-induced VLDL and LDL oxidation, was lower in citrulline-treated rats than in the standard-diet treated rats. Citrulline treatment in male aged rats favorably modulates body composition and protects against lipid oxidation and, thus, emerges as an interesting candidate to help prevent the aging process.


Citrulline treatment in male aged rats
favorably modulates body
composition and protects against lipid
oxidation and, thus, emerges as an
interesting candidate to help prevent
the aging process.


Improved Performance in Healthy Men

In a paper just published, researchers investigated the effect of oral citrulline supplementation on cycling time for trial performance in healthy men. The researchers found that citrulline reduced the time needed to complete a cycle ergometer exercise trial.2 A double-blind randomized study was used, employing 22 trained males (aged 20–49 and 25 kg/m2 ≤ body mass index < 30 kg/m2) who consumed 2.4 g/day of citrulline or placebo orally for 7 days. On Day 8 they took 2.4 g of citrulline or placebo 1 hour before a 4-km cycling time trial. The time taken to complete the 4 km cycle, along with power output/VO2 ratio (PO/VO2), plasma nitrite and nitrate (NOx) and amino acid levels, and visual analog scale (VAS) scores, was evaluated.


Oral citrulline supplementation
reduced the time take to complete a
cycle ergometer exercise trial.


Citrulline supplementation significantly increased plasma arginine levels and reduced completion time by 1.5 % compared with placebo. Additionally, citrulline significantly improved subjective feelings of muscle fatigue and concentration immediately after exercise. Oral citrulline supplementation reduced the time take to complete a cycle ergometer exercise trial.

NO plays key roles such as maintaining the function and integrity of the endothelium, including vascular tone and structure. In sports physiology, nitrate supplementation is thought to be an ergogenic aid. This view is based on evidence that NO is an important modulator of blood flow and mitochondrial respiration under physiological conditions. Some studies have shown that dietary NO related supplements, such as nitrate-rich beetroot juice, enhance human sport performance. Dietary supplementation with nitrate thus appears to be beneficial for exercise.

Interest in Citrulline Grows

There is emerging interest in the use of citrulline as an NO-related dietary ingredient. Citrulline is present in the body and is a potent endogenous precursor of arginine, which is a substrate for NO synthase (NOS). NOS catalyzes a complex enzymatic reaction that leads to NO formation from arginine and oxygen and generates citrulline as a byproduct.

Citrulline is effectively recycled via the citrulline NO cycle to arginine and plays an important role in the metabolism and regulation of NO (see Fig. 1). Citrulline supplementation has various beneficial effects, such as ameliorating arterial stiffness and improving erectile function, memory, O2 uptake kinetics, and high-intensity exercise performance through upregulation of NO synthesis.

The researchers of the ergometer exercise trial2 and others have demonstrated in animal models that oral supplementation with citrulline upregulates endothelial NO synthase (eNOS) expression, improves endothelial function, and plays an atheroprotective role.

Interestingly, a clinical trial has shown that oral intake of citrulline dose-dependently and more effectively increases plasma arginine levels than does arginine supplementation in healthy human volunteers.3 Therefore, citrulline may be considered an effective arginine and NO supplies enhancer, which has potential for enhancing sport performance.

Another study4 confirmed that 6 days of citrulline supplementation improves exercise tolerance. This suggests that chronic citrulline supplementation (for about 1 week) is needed to enhance exercise tolerance. But remember that a combination of citrulline and arginine appears to be even better for increasing arginine plasma levels.


These data indicate that athletes
competing in sports with muscular
endurance-based requirements may
potentially improve performance by
acutely supplementing citrulline.


Citrulline in Women

Citrulline malate (hereafter citrulline) is a nonessential amino acid that increases exercise performance in males. However, based on physiological differences between genders, these results cannot be generalized to females. Therefore, an investigation was performed to evaluate effects of acute citrulline supplementation on upper- and lower-body weightlifting performance in resistance-trained females.5

Fifteen females (23 ± 3 years) completed two randomized, double-blind trials consuming either citrulline (8 g dextrose + 8 g citrulline) or a placebo (8 g dextrose).

One hour after supplement consumption, the participants performed six sets each of upper- (i.e., bench press) and lower-body (i.e., leg press) exercises to failure at 80% of previously established one-repetition maximum. Immediately after each set repetitions were completed, heart rate and rating of perceived exertion (RPE) were recorded.

Repeated-measures analysis of variance indicated that subjects completed significantly more repetitions throughout upper-body exercise when consuming citrulline versus placebo (34.1 ± 5.7 vs. 32.9 ± 6.0, respectively). When consuming citrulline, similar significant improvements in total repetitions completed were observed for lower-body exercise (66.7 ± 30.5 vs. 55.13 ± 20.64, respectively). Overall the RPE score was significantly lower in upper-body exercise when subjects consumed citrulline versus placebo (7.9 ± 0.3 and 8.6 ± 0.2, respectively). The supplement consumed exhibited no significant effects on heart rate at any time point.

Acute citrulline supplementation in females increased upper- and lower-body resistance exercise performance and decreased RPE during upper-body exercise. These data indicate that athletes competing in sports with muscular endurance-based requirements may potentially improve performance by acutely supplementing citrulline.

References

  1. Moinard C, Le Plenier S, Noirez P, Morio B, Bonnefont-Rousselot D, Kharchi C, Ferry A, Neveux N, Cynober L, Raynaud-Simon A. Citrulline Supplementation induces changes in body composition and limits age-related metabolic changes in healthy male rats. J Nutr. 2015 Jul;145(7):1429-37.
  2. Suzuki T, Morita M, Hayashi T, Kamimura A. The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males. Biosci Biotechnol Biochem. 2017 Feb;81(2):372-5.
  3. Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Böger RH. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. 2008 Jan;65(1):51-9.
  4. Windmueller HG, Spaeth AE. Source and fate of circulating citrulline. Am J Physiol. 1981;241:E473–480.
  5. Glenn JM, Gray M, Wethington LN, Stone MS, Stewart RW Jr, Moyen NE. Acute citrulline malate supplementation improves upper- and lower-body submaximal weightlifting exercise performance in resistance-trained females. Eur J Nutr. 2015 Dec 11. [Epub ahead of print] PubMed PMID: 26658899.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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